Post-operative pain management is a serious issue for patients and physicians, especially in the recovery room, as the patient is waking up from the anesthesia. Too generous a dose of systemic opioid given in an attempt to control pain can potentially cause life-threatening respiratory depression. On the one hand, either too little or too late a dose of post-operative pain medication can result in the patient waling up in intolerable severe pain. In addition, it has been shown that poorly controlled post-operative pain following abdominal or thoracic surgery inhibits ventilatory movement of the chest wall abdomen, and diaphragm (P. R Bromage, Textbook of Pain, P. D. Wall, et al. (Eds.): Churchill Livingstone, 1989, pp 744-753) resulting in pulmonary atelectasis.
The existence of opioid receptors in the spinal cord was discovered in the 1970's. Following initial clinical efficacy reports in 1979 (M. Behar et al., Lancet 1:527-529, 1979), epidural opioid administration has become very popular for post-operative pain control (T. I. Ionescu et al., Act. Anaesth. Belg. 40:65-77, 1989; C. Jayr et al., Anesthesiology 78:666-676, 1993; S. Lurie, et al European Journal of Obstetrics and Gynecology and Reproductive Biology 49:147-153, 1993). Epidural opioids have the advantage of achieving good local analgesia at the spinal level without the loss of locomotor or vasomotor control or decreased level of consciousness.
Injectable opioids are widely used epidurally in post-operative and post-partum settings. Post-operative and post-partum pain usually lasts several days, but injectable opioids have relatively short durations of action (W. G. Brose et al., Pain 45:11-15, 1991; R. H. Drost et al., Arzneim-Forsch/Drug Res. 38:1632-1634, 1988; G. K. Gourlay et al., Pain 31:297-305, 1987). Thus, either continuous infusion or repeated injections are required to maintain adequate pain control (J. W. Kwan, Am. J. Hosp. Pharm. 47 (Suppl 1):S18-23, 1990; J. S. Anulty, International Anesthesiology Clinics 28:17-24, 1990; R. S. Sinatra, The Yale Journal of Biology and Medicine 64:351-374, 1991. Continuous infusion or repetitive injections further necessitate placement of catheter systems with or without attached infusion pumps, all of which consume expensive physician and nursing time for care and maintenance. Furthermore, repeated bolus injections or continuous infusions can result in respiratory depression.
Late respiratory depression and apneic episodes are the side-effects of greatest concern in early studies (P. R. Bromage, Anesthesia and Analgesia 60:461-463, 1981; E. M. Camporesi, et al., Anesthesia and Analgesia 62:633-640, 1983; T. L. Yaksh, Pain 11:293-346, 1981). A recent prospective non-randomized study of epidural morphine in 1085 patients who have undergone thoracic, abdominal, or orthopedic surgeries estimated the rate of "respiratory depression" following epidural morphine to be 0.9% (R. Stenseth et al., Acta Anaesthesiol. Scand. 29:148-156, 1985). As a comparison, the incidence of "life-threatening respiratory depression" in 860 patients given systemic morphine (PO, IV, IM, SC) was 0.9% (R. R. Miller et al, Drug Effects in Hospitalized Patients. John Wiley & Sons, New York, 1976). Prospective, randomized studies comparing epidural opioid versus systemic opioids (IM or IV) in high risk patients have shown that postoperative pain control with epidural opioid results in superior analgesia with decreased incidence of post-operative complications (N. Rawal et al., Anesth. Analg. 63:583-592, 1984; M P. Yeager, et al. Anesth. 60: 729-736, 1987).
The sustained release of various therapeutic agents after incorporation into liposomes, such as multivesicular liposomes, has been well documented both in vitro and in animals for intrathecal, subcutaneous, and intraperitoneal routes of administration, as well as in human patients for the intrathecal route of administration (S. Kim et al, J. Clin. Oncol. 11:2186-2193, 1993; V. Russack et al., Ann Neurol. 34:108-112, 1993; and M. C. Chamberlain et al., Arch Neurol. 50:261-264, 1993). However, sustained release of epidurally administered compounds has heretofore been unknown in the art.
Therefore, the need exists for new and better methods for administering opioids and other therapeutic compounds epidurally as a single dose so as to achieve a sustained release rate at therapeutically effective levels. The present invention addresses the limitations of the prior art by providing a sustained-release formulation of a therapeutic agent such as an opioid, that results in maximal analgesia immediately after a single epidural dose and provides gradually decreasing analgesia over the next several days.